The hardest parts of 1999 mode will be the very beginning and the 3-part boss encounter in Downtown Emporia. The rest isn't that bad as long as you are patient/deliberate with how you approach encounters.
Exactly what the above posters said. Nothing 1999 mode throws at you is too terrible.
But the very beginning sucks because you only get a pistol and do not have a shield, the middle of the game has a boss that is annoying as all get out on normal (much less 1999 mode), and the very ending can be infuriating. Other than that though, a cautious play style will get you through most of the game without too much difficulty.
I recommend playing it on normal or hard first though so you can get an idea of what to expect and what you want to upgrade because you have to put yourself on a tight budget for 1999 mode.
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